CD11c+ microglia promote dysfunctional T cell activation in diffuse midline glioma
Keane, L.; Baleviciute, A.; Cuesta-Marti, C.; Hincks, J.; McCarthy Hogan, M.; Sharvin, B. L.; McDermott, M.; O'Reilly, J.; Tofani, G. S. S.; du Chatinier, A.; Moloney, G. M.; Fitzgerald, P.; Foley, C.; O'Leary, O. F.; Phoenix, T. N.; Hullerman, E.; Larson, J. D.; Baker, S. J.; Clarke, G.; Cryan, J. F.
Show abstract
Paediatric diffuse midline glioma (DMG) remains refractory to immunotherapy despite T-cell infiltration, indicating that local mechanisms actively suppress anti-tumour immunity. Using complementary genetic and orthotopic mouse models, we performed lineage-resolved profiling of the DMG immune microenvironment, resolving myeloid ontogeny and microglial states by distinguishing resident microglia from infiltrating bone marrow-derived macrophages. We identified microglia as the predominant tumour-associated myeloid population and discovered selective expansion of CD11c positive; microglia exhibiting enriched antigen-presentation and immune-regulatory transcriptional programs. Tumour-infiltrating CD4+; and CD8+; T cells exhibited chronic activation and exhaustion, while ligand receptor analysis predicted inhibitory microglia T cell communication. Pharmacological CSF1R inhibition depleted CD11c positive; microglia, attenuated antigen-presentation and immune-regulatory programs, and shifted tumour-infiltrating T cells toward a less exhausted phenotype. Together, these findings identify a previously unrecognised CD11 positive; microglia T-cell axis that establishes immune dysfunction in DMG and provide a rationale for combining myeloid- and T cell-targeted immunotherapies.
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